The goal of this study is to investigate the mechanism by which RIPK1 mediates the pathology of endothelial cells and its contribution to the pathogenesis of Alzheimer's disease (AD). AD is a multifactorial and multifaceted disease with majority of demented patients display mixed AD and vascular pathology. While amyloid pathology has been recognized as a hallmark of AD, there is an increasing appreciation of the contribution from cerebrovascular pathology to AD. However, the mechanism that mediates the cerebrovascular dysfunction in AD is unclear. Most importantly, we have scarce knowledge regarding druggable targets that can be safely targeted to remedy the cerebrovascular defects for the treatment of AD. Recent studies have demonstrated that endothelial cells are able to undergo necroptosis, a form of programmed necrotic cell death that requires RIP1 Kinase (RIPK1) activity as well as RIP Kinase 3 (RIPK3) and MLKL. Furthermore, necroptosis has been implicated in mediating atherosclerosis and plaque rupture and can be targeted for both therapeutic and diagnostic interventions. RIPK1 is a key mediator of the innate immune response that regulates both inflammation and necroptosis. This study will provide important new insights into the mechanisms by which RIPK1 mediated inflammation and necroptosis contribute to the cerebrovascular pathology in AD as well as important biomarkers for the human clinical trials on RIPK1 inhibitor targeting AD. The specific aims are: Specific Aim 1: To investigate if pharmacological inhibition of RIPK1 activity can rescue cerebral microvascular pathology and functional deficits in APP/PS1 mice as that of genetic inactivation of RIPK1 that we have shown. Specific Aim 2: To investigate the mechanism of RIPK1 in mediating cerebrovascular pathology in AD. This is to investigate the cell-non-autonomous role of RIPK1 mediated inflammation and cytokine release in microglia, and the cell-autonomous role of RIPK1 in regulating the gene transcription and the release of cyclophilin A (CypA) from endothelial cells in mediating cerebrovascular pathology of APP/PS1 mice. Specific Aim 3. To investigate if blocking necroptosis in brain endothelial cells can ameliorate cerebral vascular pathology in APP/PS1 mice. This is to knockdown the expression of RIPK3 and MLKL in cerebral vascular endothelial cells of APP/PS1 mice by shRNA using an endothelial specific AAV delivery system and examine their impact on the release of CypA and vascular pathology mediated by amyloid ?.